1. Field of the Invention
The invention relates to a method of reacting a phosphoric acid, phosphonic acid or carboxylic acid derivative with an alcohol, water or NH.sub.3 in the presence of an amidine base, more particularly a method of transesterification, ammonolysis or saponification of carboxylic acid, phosphonic acid or phosphoric acid derivatives and splitting of amino acid, peptide or nucleic acid derivatives from a polymer carrier. The invention also relates to a method of saponifying a peptide ester in an aqueous medium in the presence of a base in the form of a metal compound.
2. Background Information
Various methods of transesterifyinq or saponifying the aforementioned compounds are already described in the literature. Operation is e.g. under strongly acid or basic conditions, with enzymes (D. Seebach, Angew. Chem. 1990, 102, 1363), with titanates (D. Seebach, B. Weidmann, L. Widler in "Modern Synthetic Methods", 1983), or KF/cyclic ethers (B. Lejczak, P. Kafarski, J. Szewczyk, Synthesis 1982, 412) or with ion exchange resins (W. Pereira, V. Close, W. Patton, B. Halpfern, J. Org. Chem. 1969, 34, 2032) or distannic oxanes (J. Otera, S. Ioka, H. Nozaki, J. Org. Chem. 1989, 5*, 4013). There is also a description of a method of transesterifying or saponifying ester derivatives using the amidine base DBU in solution (EP 0 110 629 and 0 150 962) or polymer-bonded (T. Ishikawa, Y. Ohsumi, T. Kawai, Bull. Chem. Soc. Jpn. 1990, 63, 819).
EP 0 110 629 Al discloses use of amidine bases for trans- esterification. The amidine is usually supported by epoxides. The citation does not mention particularly mild conditions, as necessary particularly when reacting optically active biomolecules. All the examples describe simple stable compounds without additional functional groups or optical activity.
Transesterification using calcium acetate in methanol is known from Int. J. Peptide Protein Res. 37, 1991, 451-456. In the great majority of cases, the substrates are only peptides with a C-terminal glycine radical. These peptides are insensitive to racemisation. When a C-terminal alanyl radical is used, the reaction is already inhibited. Also, this reaction requires specific protective groups. A universally applicable mild method, more particularly for reacting biomolecules, cannot be obtained by using calcium acetate.
The splitting of carboxylic acid methyl esters with DBU at 165.degree. C. in 48 hours is known from J. Org. Chem. 38, (1973), 1223-1225. These conditions are too drastic for most ester splitting, particularly for optically active esters having a center of chirality in the .alpha. position relative to the ester group.
.beta.-elimination with DBU or DBN is known from CA 114, 186011 (1991) and Tetrahedron Letters 21 (1980), 1181-1184. As is universally the case in .beta.-elimination and also mentioned in this citation, theoretically any base, even potassium hydroxide, can be used. The citation does not describe universally applicable mild reaction conditions.
All the previously-mentioned methods, except for the enzymatic method, normally require elevated temperatures, extreme pH values and/or long reaction times. Owing to the reaction conditions, most of the aforementioned methods are unsuitable for sensitive ester derivatives, e.g. containing additional functional groups or one or more chiral C atoms, more particularly compounds containing a chiral C atom in the .alpha. position relative to the ester function.